Evaluation of the phenotype of mice with NHLH2 deletion in POMC neurons

• Grant number: 23/10294-3
• Support Opportunities: Scholarships in Brazil - Support Program for Fixating Young Doctors
• Start date: August 01, 2023
• End date: June 30, 2025
• Field of knowledge: Biological Sciences - Physiology - General Physiology
• Agreement: CNPq
• Principal Investigator: Licio Augusto Velloso
• Grantee: Guilherme Augusto da Silva Nogueira
• Host Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 23/01442-9 - Evaluation of the phenotype of mice with NHLH2 deletion in POMC neurons, AP.R

Abstract

Obesity is a global epidemic due to a homeostatic imbalance between caloric intake and expenditure. Currently, there are no totally effective and safe drugs for reversing and maintaining this condition. Understanding the central mechanisms involved in energy homeostasis is important for a better comprehension of obesity, as well as for developing better therapeutic strategies. The POMC subpopulation of hypothalamic neurons plays a central role in this process, triggering increased energy expenditure and the anorexigenic effect in the postprandial period. These effects are triggered after POMC cleavage by the enzyme PC1/3 and subsequently, by the interaction of its active derivatives with MC3R and MC4R receptors present in second-order neurons. The NHLH2 transcription factor can modulate this process, since it controls PC1/3 transcription and, consequently, POMC cleavage. Studies with NHLH2 modulation models showed that this protein can influence energy homeostasis. While the inhibition of NHLH2 expression influenced the development of the obese phenotype, its overexpression proved to have a protective effect. However, the mechanisms still need to be elucidated exclusively in POMC neurons, since all studies carried out so far have had general and nonspecific technical approaches. This present study aims to evaluate the phenotype and molecular markers resulting from the modulation of NHLH2 expression, specifically in POMC neurons, using Pomc-Cre transgenic mice treated with a viral vector, exposed to a high-fat diet. We believe that the project will contribute to advances in the definition of the regulation mechanisms of energy homeostasis, as well as in the understanding and treatment of obesity.